JAK Inhibitors Show Comparable Safety to TNF Antagonists

The therapeutic landscape for immune-mediated inflammatory disorders (IMIDs) has evolved considerably with the advent of Janus kinase (JAK) inhibitors, which provide targeted immunomodulation and rapid symptom control. While these agents offer compelling benefits, safety concerns, particularly regarding cardiovascular events, thromboembolism, and malignancy, have tempered enthusiasm. The 2019 ORAL Surveillance trial highlighted these risks in older patients with rheumatoid arthritis (RA) and prompted regulatory changes, including US FDA labeling restrictions and European Medicines Agency (EMA) guidance limiting JAK inhibitor use in high-risk populations.¹

However, the ORAL Surveillance trial was deliberately focused on older patients with RA and cardiovascular comorbidities, raising questions about the generalizability of its findings to broader IMID populations or to other JAK inhibitors. To address this gap, a systematic review and meta-analysis synthesized data from 42 head-to-head comparative effectiveness studies, encompassing over 813,000 patients with IMIDs—including RA, inflammatory bowel disease (IBD), psoriasis or psoriatic arthritis (PsA), and spondyloarthropathy (SpA)—treated with JAK inhibitors or tumor necrosis factor (TNF) antagonists.²

Methods and Materials

The primary aim of this analysis was to assess the risk of 4 key safety outcomes: serious infections, malignant neoplasms, major adverse cardiovascular events (MACEs), and venous thromboembolism (VTE). The authors emphasized, “Overall findings from head-to-head comparative effectiveness studies support the safety of JAK inhibitors compared with TNF antagonists.” Importantly, these studies captured real-world usage across age groups, IMID types, and various JAK inhibitors, providing a more representative perspective than the ORAL Surveillance trial alone.

Results

In terms of serious infections, the pooled incidence rate (IR) was 3.79 per 100 person-years for JAK inhibitors versus 3.03 for TNF antagonists, with no statistically significant difference (hazard ratio [HR], 1.05; 95% CI, 0.97–1.13). Similarly, the risk of malignant neoplasms, excluding nonmelanoma skin cancers, was comparable between groups (IR 1.00 vs 0.94 per 100 person-years; HR, 1.02; 95% CI, 0.90–1.16). MACEs also showed no meaningful difference, with an IR of 0.72 versus 0.66 per 100 person-years (HR, 0.91; 95% CI, 0.80–1.04).

One notable exception emerged for VTE. Across all IMIDs, JAK inhibitors were associated with a modestly increased risk compared with TNF antagonists (HR, 1.26; 95% CI, 1.03–1.54). Subgroup analyses revealed that this risk was particularly pronounced in patients with RA (31% higher risk), whereas patients with IBD showed no significant difference. Furthermore, VTE risk appeared highest with baricitinib relative to other JAK inhibitors, underscoring potential differences linked to JAK selectivity. As the authors noted, “Although we did not observe any significant difference in the magnitude of risk of adverse events with tofacitinib or JAK1 inhibitors vs TNF antagonists for most outcomes, we observed a higher risk of VTE with baricitinib vs TNF antagonists.”

Discussion

The study’s methodology provides several strengths. By focusing exclusively on head-to-head comparative studies, the analysis mitigates confounding introduced by noncomparative observational designs. Extensive subgroup analyses and meta-regression allowed for nuanced examination of factors such as age, sex, comorbidities, IMID type, and JAK inhibitor class. However, limitations persist. The included studies were primarily retrospective, with follow-up durations shorter than the ORAL Surveillance trial. Outcome ascertainment relied on administrative claims and medical record review, which may under- or overestimate events relative to adjudicated trial data. Furthermore, patient-level data were limited, constraining precise attribution of adverse events to medication versus disease activity.

Conclusion

This comprehensive synthesis suggests that, outside the high-risk populations defined in ORAL Surveillance, JAK inhibitors demonstrate comparable safety to TNF antagonists for serious infections, malignancy, and MACEs, with only a modest VTE signal in RA. These findings provide clinicians with a broader evidence base to inform individualized treatment decisions, highlighting the importance of patient selection, monitoring, and balancing efficacy with safety. The authors advocate that, “Further research, especially long-term studies, is needed to fully elucidate the safety of these agents across diverse populations and optimize clinical use.”

This work underscores a critical message for clinical practice: while regulatory caution remains warranted for high-risk individuals, JAK inhibitors may offer a safe and effective therapeutic option across a wide spectrum of IMIDs, reinforcing the need to tailor treatment strategies to individual patient risk profiles.

References

1. Curtis JR, Yamaoka K, Chen YH, et al. Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis. 2023;82(3):331-343. doi:10.1136/ard-2022-222543
2. Solitano V, Ahuja D, Lee HH, et al. Comparative safety of JAK inhibitors vs TNF antagonists in immune-mediated inflammatory diseases: A systematic review and meta-analysis. JAMA Netw Open. 2025;8(9):e2531204. Published 2025 Sep 2. doi:10.1001/jamanetworkopen.2025.31204